Safety, Pharmacokinetics and Clinical Activity of Oral Rigosertib in Solid Tumors
This is a phase 1 study in which 2 to 72 patients with advanced cancer will receive oral doses of rigosertib, a new investigational (unapproved) anti-cancer drug. The objective of the study is to determine the highest dose of drug that can be given safely. The study will start by testing a low dose. If this dose is safe, then, higher and higher doses will be tested as long as the previous lower dose was safe. Safety will be determined by looking for any side effects or unusual laboratory values. It is important to know the highest safe dose so that additional studies can be done. The drug will be given in the form of capsules twice or three times a day for 21 consecutive days of 21-day cycles.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 1 Study To Assess The Tolerability, Pharmacokinetics and Clinical Activity of Rigosertib Administered Orally as Escalating Multiple Doses Twice or Three Times a Day up to 21 Days of a 21-Day Cycle in Patients With Advanced Cancer|
- Adverse Events [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]Adverse events (AEs) will be regarded as treatment emergent signs and symptoms (TESS) if they started on or after the date and time of administration of the first dose of study drug, or if they were present prior to the administration of the first dose of study drug and increased in severity during the study. Adverse events include clinical laboratory parameters (e.g., Hematology Panel and Serum Chemistry Panel). Other safety parameters include vital signs, physical examination findings, concomitant medications, and drug exposure.
- Concentration of ON 01910.Na in plasma [ Time Frame: 2 years ] [ Designated as safety issue: No ]The concentration of ON 01910.Na in plasma at various times after administration will be used to derive the following PK parameters for ON 01910.Na using model-independent analysis as appropriate for the data: Tmax, Cmax, t½, AUC0-t, AUC 0-α, CL, and Vss.
- Measurement of tumor size [ Time Frame: 2 years ] [ Designated as safety issue: No ]Tumor response rates will be evaluated for each patient using RECIST criteria.
- Concentration of ON 01910.Na in Urine [ Time Frame: 1 years ] [ Designated as safety issue: No ]Urine PK samples to determine ON 01910.Na urinary concentrations will be collected on Day 1 and Day 21 of the first cycle, and on Day 15 of the second cycle in all patients and will include the predose void volume and a 24-hr post-dose urine collection over the 0-4 hr, 4-8 hr, and 8-24 hr intervals.
|Study Start Date:||July 2010|
|Estimated Study Completion Date:||August 2013|
|Estimated Primary Completion Date:||May 2013 (Final data collection date for primary outcome measure)|
Doses of rigosertib up to 700 mg twice a day or three times a day every day of 21-day cycles.
Doses of rigosertib up to 700 mg twice a day or three times a day for 21 days of 21-day cycles. Treatment may continue until progression.
Patients will be initially enrolled in two-patient cohorts starting with a 70 mg bid dosing.
- In the absence of drug-related grade 2 or higher toxicity in the two patients treated for an entire 21-day first cycle, the next two patients will be receiving a dose escalated by 100% from prior dose.
- If drug-related grade 2 or higher toxicity is observed in at least one of the two patients treated for a full 21-day cycle, the cohort will be expanded in order to obtain 3 evaluable (treated for an entire 21-day first cycle) patients.
- If no dose limiting toxicity (DLT) is observed in the first three patients treated for an entire 21-day first cycle, then the next three patients will be enrolled at a dose level increased by approximately 50% from prior dose.
- If one DLT is observed in the first three patients treated for an entire 21-day first cycle, then the three next patients will be enrolled at the same dose level.
- If no more than one DLT is observed in the six patients treated for an entire 21-day cycle, then the next six patients will be administered a dose level increased by approximately 25% from prior dose.
- If two or more patients in any cohort experience DLT, then the maximum tolerated dose (MTD) will have been exceeded and no further dose escalation will occur. The MTD will be established as the immediate prior dosing level
- Identical rules will be applied to all cohorts of patients recruited to the study.
- A total of up to 24 patients may be treated at the MTD dose level in order to obtain data on the onset and severity of dysuria symptoms in approximately 12 patients including about 6 patients who will be treated with oral sodium bicarbonate at the time of treatment initiation (early treatment) and ~6 patients who will be treated with oral sodium bicarbonate at the time of symptom onset (late treatment). Alternating patients on a 1-to-1 basis by enrollment date will receive oral sodium bicarbonate as 650 mg tablets given twice daily with two 8-ounce glasses of water 1 hour after rigosertib administration, either at the time of study initiation (early treatment) or at the time of urinary symptom onset (late treatment).
Three additional cohorts will be treated with multiple escalating doses administered orally three time daily (TID) (140 mg, 280 mg and 420 mg) for 21 consecutive days of a 21-day cycle using identical rules as those described above (ie, starting with 2-patient cohorts at 140 mg dosing and expanding to 3-6 patient cohorts if at least 1 Grade 2 or higher drug-related toxicity is observed in 2-patient cohorts).
Up to 12 patients may be treated at the MTD level identified with TID dosing.
Prior to escalating to the next planned dose level, a designated Cohort Review Committee (CRC) consisting of the Principal Investigators (or their representatives), the Medical Monitor and the Sponsor's Medical Representative will review all available safety data over the 21 day duration of Course 1 for the previous cohort. Additional input may be provided from the study monitors, pharmacokinetic or toxicology specialists as required. The CRC also has to ability to recommend dose de-escalation for ON 01910.Na if warranted by the observed toxicity profile.
|United States, Colorado|
|University of Colorado at Denver Health and Sciences|
|Denver, Colorado, United States, 80045|
|Principal Investigator:||Antonio Jimeno, MD, PhD||University of Colorado at Denver Health and Sciences|